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Type: Artigo de periódico
Title: Alzheimer-associated A Beta Oligomers Impact The Central Nervous System To Induce Peripheral Metabolic Deregulation
Author: Clarke
Julia R.; Lyra e Silva
Natalia M.; Figueiredo
Claudia P.; Frozza
Rudimar L.; Ledo
Jose H.; Beckman
Danielle; Katashima
Carlos K.; Razolli
Daniela; Carvalho
Bruno M.; Frazao
Renata; Silveira
Marina A.; Ribeiro
Felipe C.; Bomfim
Theresa R.; Neves
Fernanda S.; Klein
William L.; Medeiros
Rodrigo; LaFerla
Frank M.; Carvalheira
Jose B.; Saad
Mario J.; Munoz
Douglas P.; Velloso
Licio A.; Ferreira
Sergio T.; De Felice
Fernanda G.
Abstract: Alzheimer's disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD-associated A beta oligomers (A beta Os) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. Systemically injected A beta Os failed to induce glucose intolerance, suggesting A beta Os target brain regions involved in peripheral metabolic control. Accordingly, we show that A beta Os affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2 alpha phosphorylation (eIF2 alpha-P). A beta Os further induced eIF2 alpha-P and activated proinflammatory IKK beta/NF-kappa B signaling in the hypothalamus of mice and macaques. A beta Os failed to trigger peripheral glucose intolerance in tumor necrosis factor-alpha (TNF-alpha) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented glucose intolerance in mice, indicating that A beta Os act via a central route to affect peripheral glucose homeostasis. While the hypothalamus has been largely ignored in the AD field, our findings indicate that A beta Os affect this brain region and reveal novel shared molecular mechanisms between hypothalamic dysfunction in metabolic disorders and AD.
Subject: Endoplasmic-reticulum Stress
Induced Insulin-resistance
D-aspartate Receptor
Diet-induced Obesity
Mouse Model
Cognitive Impairment
Country: HOBOKEN
Citation: Alzheimer-associated A Beta Oligomers Impact The Central Nervous System To Induce Peripheral Metabolic Deregulation. Wiley-blackwell, v. 7, p. 190-210 FEB-2015.
Rights: embargo
Date Issue: 2015
Appears in Collections:Unicamp - Artigos e Outros Documentos

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